Interferon gamma inducible protein 10 (IP-10) (also known as CXCL10) is a 10 kDa chemokine that was originally identified based on expression of the IP-10 gene in cells treated with interferon gamma (IFN-gamma) (Luster, A. D. et al. (1985) Nature 315:672-676). IP-10 shows homology to proteins having chemotactic activity, such as platelet factor 4 and beta-thromoboglobulin, and to proteins having mitogenic activity, such as connective tissue-activating peptide III (Luster, A. D. et al. (1987) Proc. Natl. Acad. Sci. USA 84:2868-2871). IP-10 is secreted by a variety of cells, including endothelial cells, monocytes, fibroblasts, and keratinocytes, in response to IFN-gamma (Luster, A. D. and Ravetch, J. V. (1987) J. Exp. Med. 166:1084-1097). IP-10 also has been shown to be present in dermal macrophages and endothelial cells in delayed type hypersensitivity (DTH) responses in human skin (Kaplan, G. et al. (1987) J. Exp. Med. 166:1098-1108). Although originally identified based on its being induced by IFN-gamma, IP-10 also can be induced by IFN-alpha, for example in dendritic cells (Padovan, E. et al. (2002) J. Leukoc. Biol. 71:669-676). IP-10 expression can also be induced in cells of the central nervous system, such as astrocytes and microglia, by stimuli such as IFN-gamma, viruses and lipopolysaccharide (Vanguri, R. and Farber, J. M. (1994) J. Immunol. 152:1411-1418; Ren, L. Q. et al. (1998) Brain Res. Mol. Brain. Res. 59:256-263). The immunobiology of IP-10 is reviewed in Neville, L. F et al. (1997) Cytokine Growth Factor Rev. 8:207-219.
The receptor for IP-10 has been identified as CXCR3, a seven transmembrane receptor (Loetscher, M. et al. (1996) J. Exp. Med. 184:963-969). CXCR3 has been shown to be expressed on activated T lymphocytes but not on resting T lymphocytes, nor on B lymphocytes, monocytes or granulocytes (Loetscher, M. et al., supra). CXCR3 expression has been shown to be upregulated on NK cells by stimulation with TGF-beta 1 (Inngjerdingen, M. et al. (2001) Blood 97:367-375). Two other ligands for CXCR3 have also been identified: MIG (Loetscher, M. et al., supra) and ITAC (Cole, K. E. et al. (1998) J. Exp. Med. 187:2009-2021).
Binding of IP-10 to CXCR3 has been shown to mediate calcium mobilization and chemotaxis in activated T cells (Loetscher, M. et al., supra). Chemotaxis and intracellular calcium mobilization are also induced by IP-10 binding to CXCR3 on activated NK cells (Maghazachi, A. A. et al. (1997) FASEB J. 11:765-774). Within the thymus, IP-10 has been shown to be a chemoattractant for TCRαβ+ CD8+ T cells, TCRγδ+ T cells and NK-type cells (Romagnani, P. et al. (2001) Blood 97:601-607).
IP-10 or its receptor CXCR3 have been identified in a variety of different inflammatory and autoimmune conditions, including multiple sclerosis (see e.g., Sorensen, T. L. et al. (1999) J. Clin. Invest. 103:807-815), rheumatoid arthritis (see e.g., Patel, D. D. et al. (2001) Clin. Immunol. 98:39-45), ulcerative colitis (see e.g., Uguccioni, M. et al. (1999) Am. J. Pathol. 155:331-336), hepatitis (see e.g., Narumi, S. et al. (1997) J. Immunol. 158:5536-5544), spinal cord injury (see e.g., McTigue, D. M. et al. (1998) J. Neurosci. Res. 53:368-376; Gonzalez et al. 2003. Exp. Neurol. 184:456-463), systemic lupus erythematosus (see e.g., Narumi, S. et al. (2000) Cytokine 12:1561-1565), transplant rejection (see e.g., Zhang, Z. et al. (2002) J. Immunol. 168:3205-3212), Sjogren's syndrome (see e.g., Ogawa, N. et al. (2002) Arthritis Rheum. 46:2730-2741). Accordingly, therapeutic agents that inhibit the activity are desirable, in particular agents that are suitable for use in humans.